Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_001306179.2:c.761T>A

CA386965978

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: ec54304f-5944-4ef8-8f22-f7f581be526d

HGVS expressions

NM_001306179.2:c.761T>A

NC_000012.12:g.120994211T>A

CM000674.2:g.120994211T>A

NC_000012.11:g.121432014T>A

CM000674.1:g.121432014T>A

NC_000012.10:g.119916397T>A

NG_011731.2:g.20466T>A

ENST00000257555.11:c.761T>A

ENST00000257555.10:c.761T>A

ENST00000400024.6:c.761T>A

ENST00000402929.5:n.896T>A

ENST00000535955.5:n.43-3280T>A

ENST00000538626.2:n.191-3280T>A

ENST00000538646.5:c.574T>A

ENST00000540108.1:c.*201T>A

ENST00000541395.5:c.761T>A

ENST00000541924.5:c.713+505T>A

ENST00000543427.5:c.633+585T>A

ENST00000544413.2:c.761T>A

ENST00000544574.5:c.73-2406T>A

ENST00000560968.5:n.893+11T>A

ENST00000615446.4:c.-257-2051T>A

ENST00000617366.4:c.586+632T>A

NM_000545.5:c.761T>A

NM_000545.6:c.761T>A

NM_001306179.1:c.761T>A

NM_000545.8:c.761T>A

Uncertain Significance

PM2_Supporting PS3_Supporting PM1_Supporting PP3

PM5 PP4 PP1

Evidence Links 1

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.761T>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to glycine at codon 254 (p.(Leu254Gln)) of NM_000545.8. This variant is located within a conserved region of the HNF1A DNA binding domain (codons 107-174 and 201-280), which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting) and is predicted to be deleterious by computational evidence, with a REVEL score of 0.931 (PP3), which is greater than or equal to the MDEP threshold of 0.70. Functional studies demonstrated the p.Leu254Gln protein has transactivation below 40% of wildtype (PMID: 26431509; PS3_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (PMID: 26431509). Additionally, one independent occurrence does not meet the MDEP cutoff for PS4_Moderate. Another missense variant, c.760C>A p.Leu254Met, has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.761T>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PM2_Supporting, PP3, PM1_Supporting, PS3_Supporting).

PM2_Supporting

absent gnomAD

PS3_Supporting

22% transcriptional activity in vitro (PMID: 26431509).

transcriptional assay 22% activity PubMed:26431509

PM1_Supporting

This variant is located within a conserved region of the HNF1A DNA binding domain (codons 107-174 and 201-280), which is defined as critical for the protein’s function by the ClinGen MDEP.

PP3

REVEL 0.931

PM5

Another missense variant, c.760C>A p.Leu254Met, has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied.

PP4

This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (PMID: 26431509).

PP1

Family members in PMID: 26431509 has CHI, not sufficient evidence to say that this is part of the HNF1A phenotype so will not apply.

Approved on: 2022-06-28

Published on: 2022-06-28

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